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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis
New England Journal of Medicine, Volume 365, No. 7, Year 2011
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Description
BACKGROUND: Generalized pustular psoriasis is a life-threatening disease of unknown cause. It is characterized by sudden, repeated episodes of high-grade fever, generalized rash, and disseminated pustules, with hyperleukocytosis and elevated serum levels of C-reactive protein, which may be associated with plaque-type psoriasis. METHODS: We performed homozygosity mapping and direct sequencing in nine Tunisian multiplex families with autosomal recessive generalized pustular psoriasis. We assessed the effect of mutations on protein expression and conformation, stability, and function. RESULTS: We identified significant linkage to an interval of 1.2 megabases on chromosome 2q13-q14.1 and a homozygous missense mutation in IL36RN, encoding an interleukin- 36-receptor antagonist (interleukin-36Ra), an antiinflammatory cytokine. This mutation predicts the substitution of a proline residue for leucine at amino acid position 27 (L27P). Homology-based structural modeling of human interleukin-36Ra suggests that the proline at position 27 affects both the stability of interleukin-36Ra and its interaction with its receptor, interleukin-1 receptor-like 2 (interleukin-1 receptor- related protein 2). Biochemical analyses showed that the L27P variant was poorly expressed and less potent than the nonvariant interleukin-36Ra in inhibiting a cytokine- induced response in an interleukin-8 reporter assay, leading to enhanced production of inflammatory cytokines (interleukin-8 in particular) by keratinocytes from the patients. CONCLUSIONS: Aberrant interleukin-36Ra structure and function lead to unregulated secretion of inflammatory cytokines and generalized pustular psoriasis. (Funded by Agence Nationale de la Recherche and Société Française de Dermatologie.) Copyright © 2011 Massachusetts Medical Society.
Authors & Co-Authors
Marrakchi, Slaheddine
Tunisia, Sfax
Chu Hedi-chaker
France, Paris
Inserm
Guigue, Philippe
France, Paris
Inserm
Renshaw, Blair R.
United States, Thousand Oaks
Amgen Incorporated
Puel, Anne
France, Paris
Inserm
Pei, Xue Yuan
United Kingdom, Cambridge
University of Cambridge
Fraïtag, Sylvie R.
France, Paris
Inserm
France, Paris
Hôpital Necker Enfants Malades
Zribi, J.
Tunisia, Sfax
Chu Hedi-chaker
Bal, Elodie
France, Paris
Inserm
Cluzeau, C.
France, Paris
Inserm
Chrabieh, Maya
France, Paris
Inserm
Towne, Jennifer E.
United States, Thousand Oaks
Amgen Incorporated
Douangpanya, Jason
United States, Thousand Oaks
Amgen Incorporated
Pons, Christian
France, Paris
Institut Pasteur, Paris
Mansour, Sourour
France, Paris
Inserm
Serre, Valérie
France, Paris
Inserm
Makni, Hafedh
Tunisia, Sfax
Chu Hedi-chaker
Mahfoudh, Nadia
Tunisia, Sfax
Chu Hedi-chaker
Fakhfakh, Faiza
Tunisia, Sfax
Chu Hedi-chaker
Bodemer, Christine
France, Paris
Inserm
Feingold, Josué A.
France, Paris
Inserm
Hadj-Rabia, Smaïl
France, Paris
Inserm
Favre, Michel
France, Paris
Institut Pasteur, Paris
Geńin, Emmanuelle
France, Paris
Inserm
Sahbatou, Mourad
France, Paris
Fondation Jean Dausset - Ceph
Münnich, Arnold
France, Paris
Inserm
Casanova, Jean Laurent
France, Paris
Inserm
United States, New York
Rockefeller University
Sims, John E.
United States, Thousand Oaks
Amgen Incorporated
Turki, Hamaida
Tunisia, Sfax
Chu Hedi-chaker
Bachelez, Hervé
France, Paris
Inserm
Smahi, Asma
France, Paris
Inserm
Statistics
Citations: 802
Authors: 30
Affiliations: 8
Identifiers
Doi:
10.1056/NEJMoa1013068
ISSN:
00284793
e-ISSN:
15334406
Research Areas
Cancer